The overall objective of this proposal is to elucidate the triggering mechanism for proliferation of medial smooth muscle cells (SMC) in the intima of the artery during development of the atherosclerotic lesion. Bovine, swine, and human arterial cells in culture will be employed in the pursuit of this objective, with an ultimate goal of establishing the in vivo relevance of the in vitro observations. Two interrelated general hypotheses will be tested by the proposed studies. The first is that cell-cell communication plays an important role in the proliferative activity of SMC. Specifically we propose that endothelial cell (EC) and macrophage-monocyte (MDM) products govern the multiplication of SMC. The second hypothesis is that SMC proliferation is composed of two separate events, modulation and mitogenesis, and that each process is regulated by cell-derived or blood-borne factors. We propose to examine these hypotheses by pursuing the following goals: (i) to identify by both cocultivation and conditioned media experiments factors or conditions which regulate the production of endothelial-derived growth factor (EDGF) by EC and macrophage-derived growth factor by MDM, (ii) to characterize a factor in EDGF preparations that competes for binding of the platelet-derived growth factor (PDGF) to its cell surface receptor, (iii) to determine whether EC or MDM possess latent high affinity cell surface receptors for PDGF or EDGF, (iv) to establish an assay, using monoclonal antibodies or labelled hormones, for the conversion of a SMC culture from contractile state to synthetic state cells (modulation process), and (v) to identify factors or conditions which regulate SMC modulation. The proposed research should shed some light on the role of cell-cell communication in the growth control of vascular cells, and help to elucidate the molecular mechanism of one step in atherogenesis.